Our mission is to improve quality of life and longevity, through better prevention, diagnosis and treatment of heart failure, including the establishment of networks for its management, education and research.

Case Presentation:
A 33-year-old woman was referred to our hospital with a history of exertional dyspnea and palpitations. Congestive heart failure had been diagnosed and treated pharmacologically for 1 year. A complete atrioventricular block developed 3 months before admission and a DDD pacemaker was implanted in another hospital. A chest radiograph was normal without signs of lymphadenopathy or reticulonodularity in either lung field.

Topic(s):

Myocardial Disease

Transthoracic echocardiography revealed a dilated left ventricle with a reduced ejection fraction of 30%. The patient underwent coronary angiography, which showed normal epicardial coronary arteries. Despite medical treatment for heart failure, the clinical status did not improve, and she was referred to our department for further investigation of the underlying heart disease.

On admission, the patient complained of dyspnea on exertion, and heart failure was categorized as NYHA class III. Clinical examination revealed an irregular pulse at 110 beats per min and a blood pressure of 110/70 mm Hg. Chest auscultation was normal. There was a mild pansystolic murmur consistent with mitral regurgitation. No other signs of congestive heart failure were evident. A treadmill test had to be terminated at 75 W due to dyspnea.

Echocardiography showed a markedly dilated left ventricle with an end-diastolic diameter of 76 mm. The interventricular septal thickness was 7 mm, and the left ventricular posterior wall was 9 mm. The left ventricular ejection fraction was estimated as 25%, and a moderate mitral regurgitation was observed. Transesophageal echocardiography was undertaken to further assess the severity of mitral regurgitation and to exclude a source of thromboembolism. The mitral leaflets were structurally unaltered, and the mechanism of mitral regurgitation was attributed to annular dilatation. The echogenicity of the myocardium appeared normal.

A 12-lead electrocardiogram showed atrial fibrillation and a left bundle branch block. A Holter electrocardiogram recording performed showed several self-limiting episodes of torsade de pointe ventricular tachycardia (fig. 1). On the following day, the patient was resuscitated due to ventricular fibrillation. Within the next 12 h, several episodes of ventricular tachycardia were observed and successfully terminated by electrical cardioversion.

What do you think is the diagnosis in this patient, which further investigations should be performed?

Diagnosis, case resolution and treatment

The patient underwent a second coronary angiography in which endomyocardial biopsies from the interventricular septum and the left ventricle were taken. The biopsies showed histopathological evidence of cardiac sarcoidosis ( fig. 1a ). Nonnecrotizing granulomas were composed of epitheloid cells, moderate numbers of multinucleated giant cells containing asteroid bodies and scattered lymphocytes. The florid granulomas appeared to replace and destroy cardiac myofibrils and were surrounded by abundant fibrous tissue. Immunohistochemically, T cells were detected as an intense rim-like staining of CD3-positive cells localized around the center of the granulomas ( fig. 1b).

Negative results were obtained from polymerase chain reactions in cardiac tissue for genomic sequences of entero-, parvo B19, influenza, herpes, adeno- and Epstein-Barr viruses and for Chlamydia pneumoniae, Borrelia burgdorferi and Mycobacterium tuberculosis. Special stainings for infectious organisms were negative.

Fig. 1a: Fig.1b:

Chest computed tomography (CT), including high-resolution images, showed no typical features of pulmonary sarcoid. Transbronchial biopsies showed no signs of lung involvement, and the ratio of CD4/CD8 cells in bronchoalveolar fluid was normal (0.5, normal range 0.4–1.8). Investigation of other organs revealed an absence of systemic involvement including lymphadenopathy and ocular, neurological and cutaneous lesions. Sonography of the right kidney showed a loss of parenchyma due to recurrent episodes of chronic pyelonephritis in the past. The activity of angiotensin-converting enzyme was 22 U/l (normal range 18–55), and the serum creatinine level was slightly increased (1.1 mg/ml, normal range 0.4–1.0). Serum troponin T levels were normal.
Sequencing of the patient’s btnl2 gene revealed a homozygous G - A transition in exon 5 constituting the sarcoidosis-associated risk variant rs2076530 ( fig. 2).

Fig 2:Electropherogram showing a homozygous
G ] A transition (underlined) in exon 5 of the patient’s btnl2 gene. The mutated gene codes for a splice variant which lacks the carboxy-terminal immunoglobulin-like constant domain and the transmembrane helix. The truncating splice site mutation (rs2076530) has been identified as a risk factor for sarcoidosis.

With regard to the arrhythmias, loading with amiodarone was efficient to suppress the tachyarrhythmias, and the patient became hemodynamically stable within the next days. Weaning from the respirator proceeded without complications. When extubated, the patient was fully orientated but suffered from a minor form of retrograde amnesia.
Immediately after diagnosing cardiac sarcoidosis, the patient was administered high doses of oral corticosteroids (initially prednisolone at 250 mg per day). The DDD pacemaker device was upgraded to a biventricular resynchronization system including an implanted cardioverter defibrillator. Under treatment with amiodarone and steroids, no further episodes of ventricular tachycardia occurred.

Discussion

Isolated cardiac sarcoidosis has been described in a few case reports, but is extremely rare and usually preceded future involvement of other organs [1, 3, 5] . Sarcoid heart disease without evidence of systemic manifestation is a diagnostic challenge for the treating physician, because most of the noninvasive diagnostic procedures performed are unable to detect granulomatous infiltrates in the myocardium. Routine imaging techniques such as echocardiography allow the assessment of global or segmental left ventricular dysfunction, but frequently fail to reveal signs of myocardial inflammation.

Recently, cardiac magnetic resonance imaging (MRI) has been suggested as a promising and comprehensive investigation for the early diagnosis of cardiac sarcoidosis [9, 10]. Although MRI provides a reliable estimation of the extent of cardiac involvement, data on how accurate the technique differs between sarcoid lesions and other forms of inflammatory heart diseases are not available. Moreover, not for all patients, such as in our case, is MRI a suitable diagnostic procedure. Laboratory tests for elevated serum levels of angiotensinconverting enzyme, although a common finding in sarcoidosis, are difficult to interpret in heart failure patients who are commonly on medication with angiotensin-converting enzyme inhibitors [11]. Measuring troponin levels does not add further strength to the differential diagnosis of sarcoidosis, since they are usually normal, as also seen in our patient [12]. As in our case, endomyocardial biopsy is very useful in diagnosing isolated cardiac manifestation of the disease. However, a negative biopsy does not rule out sarcoid heart disease due to a patchy or focal distribution of granulomas and the limited diagnostic sensitivity of the procedure [7, 13, 14].

In a recently published genetic study, sarcoidosis has been linked to a truncating splice variant in the btnl2 gene [8]. The authors reported that a point mutation in the btnl2 gene introduces a cryptic splice site located 4 base pairs upstream of the affected wild-type donor site that generated a mutant protein with a premature stop codon. The truncated BTNL2 protein lacks a membraneanchoring domain and exhibits disrupted membrane localization. BTNL2 is expressed in cells of the immune system and has been implicated as a receptor molecule involved in the control of T cell proliferation. Loss of membrane localization appears to impair the inhibitory immunoregulatory function of BTNL2. Thus, the altered intracellular distribution of mutant BTNL2 may account for the exaggerated cellular immune response and increased inflammatory activity of macrophages seen in sarcoidosis. In the study population from the German sarcoidosis consortium, the odds ratio of the susceptibility allele rs2076530 was 1.60 in heterozygotes and 2.75 in homozygotes, suggesting only a moderate influence on the individual risk level [8].
Nonetheless, identifying the risk-associated single nucleotide polymorphism may help to predict sarcoidosis as the underlying cause of heart failure. Particularly, younger patients, who are at a low risk of ischemic cardiomyopathy, may benefit from a refined diagnostic strategy that includes the routine testing of the btnl2 haplotype.

Conclusion:

Early diagnosis of cardiac sarcoidosis is important, because the prevalence of ventricular tachycardia and a complete heart block is high among these patients. Sudden cardiac death due to ventricular fibrillation may be the first symptom of the disease and many cases of isolated heart involvement are only diagnosed postmortem.

Other signs of cardiac involvement include left ventricular enlargement, wall motion abnormalities of localized or diffuse nature and diastolic stiffness of the ventricular wall, papillary muscle dysfunction and pericardial effusion. As in our case, endomyocardial biopsy is useful in diagnosing isolated cardiac manifestation of the disease.

However, a negative biopsy does not rule out sarcoid heart disease due to a patchy or focal distribution of granulomas and the limited diagnostic sensitivity of the procedure [7, 13, 14]. Screening for the respective haplotype may help to identify patients with heart failure caused by sarcoid infiltration of the myocardium. Treatment with high doses of corticosteroids appears to prevent the remodeling of the myocardial tissue and improves left ventricular function [6, 15].